ABSTRACT The overall aim of this study is to investigate multi-omic profiles for successful cognitive aging in adults with Down syndrome (DS). Virtually all adults with DS develop Alzheimer disease (DS-AD) associated neuropathology by 40 years of age, with risk of dementia increasing rapidly from late 40s or early 50s. Yet, there is a wide range of age at onset of dementia, and there is a group of adults older than 60 years of age who do not develop dementia. The search for preclinical, diagnostic and prognostic biomarkers for neurodegenerative diseases has grown exponentially, but other than A?, little is known about biomarkers that characterize risk or are protective for disease onset in DS or why some individuals with DS remain dementia-free altogether. We have identified a group of high-risk adults with DS who have not developed dementia despite their advanced age, as well as a group of adults with DS who developed dementia at a relatively young age. We propose to leverage existing longitudinal clinical data and biosamples to contrast these extreme phenotypes in order to identify proteomic, metabolomic and genomic markers of relative protection and susceptibility in this cohort with known high genetic risk for DS-AD. To accomplish this goal, we will use a large cohort of adults with DS that has been followed prospectively in a DS Program Project study (P01HD035897). Specifically, we will: (1) characterize older, non-demented vs. the remaining cohort, particularly younger, demented adults with DS to generate a metabolomic profile of successful cognitive aging; (2) Identify proteins that distinguish older non-demented adults with DS from the remaining cohort, particularly younger, demented adults to generate proteomic profiles of successful cognitive aging; (3) Identify genetic variants or genes that are associated with protective metabolomic and proteomic profiles identified from Aims 1 and 2, and then perform data-driven multi-omic analysis; (4) Using the protective factors identified from Aims 1-3, we will examine the associations between protective biomarker profiles and neuropsychological and functional performance scores. Once protective factors identified, we will confirm our findings using independent, external DS and non-DS cohorts.